采用新型微泡技术靶向AC005229.4/Cul1抑制肝癌对索拉非尼耐药的研究
Inhibition of liver cancer resistance to sorafenib by targeting AC005229.4/Cul1 with novel microbubble technology
投稿时间:2024-09-03  修订日期:2025-02-21
DOI:
中文关键词:  液态氟碳纳米粒  索拉非尼  耐药  晚期肝癌  LncRNA
英文关键词:liquid fluorocarbon nanoparticles  Sorafenib  Drug resistance  Advanced liver cancer  LncRNA
基金项目:国家自然科学基金项目(面上项目,重点项目,重大项目)
作者单位邮编
牟瑞姝 哈尔滨医科大学附属肿瘤医院消化内科一病房 150081
李雪东 哈尔滨医科大学附属肿瘤医院消化内科一病房 150081
周雨昕 哈尔滨医科大学附属肿瘤医院消化内科一病房 150081
谢蕊* 哈尔滨医科大学附属肿瘤医院消化内科一病房 150081
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中文摘要:
      [目的]探究索拉非尼治疗晚期肝癌的耐药机制, 寻觅新分子靶点为提升索拉非尼疗效提供新策略。 [方法]通过数据库及生信分析,锁定Cul1为索拉非尼耐药关键因子,其所在泛素化连接酶SKP1-Cul1-F-box(SCF)复合物可促肝癌细胞增殖。AC005229.4是Cul1基因启动子区反义链转录出来的lncRNA,能促进Cul1表达,筛选出miR-520b-3p可直接靶向Cul1及抑制AC005229.4间接下调Cul1。构建多功能液态氟碳纳米粒(PFH/ICG/miR-520b-3p/PLGA-PEI)携miR-520b-3p靶向AC005229.4/Cul1以抑制Cul1表达、增加索拉非尼药敏性。 [结果]成功构建了多模态成像功能的液态氟碳纳米粒,体内外实验显示,纳米粒释放的miR-520b-3p有效抑制Cul1表达,提升索拉非尼耐药肝癌细胞药敏性。 [结论]采用新型微泡技术靶向AC005229.4/Cul1,可抑制Cul1表达、提升肝癌的索拉非尼耐药细胞的药敏性,为晚期肝癌靶向研究与治疗提供重要理论基础和有效的技术手段。
英文摘要:
      [Objective] To investigate the mechanisms of resistance to sorafenib in the treatment of advanced liver cancer and identify novel molecular targets, thereby providing new strategies to enhance the efficacy of sorafenib. [Methods] Utilizing database searches and bioinformatics analyses, Cul1 was identified as a key factor in sorafenib resistance, with its ubiquitin ligase complex, SKP1-Cul1-F-box (SCF), promoting proliferation in liver cancer cells. AC005229.4, an lncRNA transcribed from the antisense strand of the Cul1 gene promoter region, enhances Cul1 expression. miR-520b-3p was screened for its ability to directly target Cul1 and indirectly downregulate Cul1 by inhibiting AC005229.4. A multifunctional liquid perfluorocarbon nanoparticle (PFH/ICG/miR-520b-3p/PLGA-PEI) was constructed to carry miR-520b-3p targeting AC005229.4/Cul1, thereby inhibiting Cul1 expression and increasing sensitivity to sorafenib. [Results] A liquid perfluorocarbon nanoparticle with multimodal imaging capabilities was successfully constructed. Both in vitro and in vivo experiments demonstrated that the miR-520b-3p released from the nanoparticle effectively inhibited Cul1 expression and enhanced the sensitivity of sorafenib-resistant liver cancer cells to the drug. [Conclusion] Utilizing novel microbubble technology to target AC005229.4/Cul1 can inhibit Cul1 expression and enhance the sensitivity of sorafenib-resistant liver cancer cells, providing an important theoretical foundation and effective technical means for targeted research and treatment of advanced liver cancer.
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